ABSTRACT Nanosensor technology for continuous monitoring of proteins in vivo would enable researchers to track the dynamics of biomolecule expression as it pertains to disease pathogenesis or predicting therapeutic efficacy, with results available in real-time. An example where this diagnostic ability would be groundbreaking is in the context of understanding cytokine release syndrome (CRS). CRS is a systemic inflammatory response that arises when the immune system is overstimulated, leading to extreme toxic events such as multiple organ dysfunction1. There is now increasing evidence to suggest that the development of severe cases of COVID-19 can be attributed to onset of CRS. It has been revealed that serum levels of cytokines like IFN?, IL-6, sIL-2R?, and IL-10 can be significantly elevated in patients with severe CRS, before the apparent onset of severe symptoms. However, the use of cytokines as biomarkers of CRS would require a rapid, minimally invasive diagnostic assay, which is currently unavailable, slowing animal studies of COVID-19/CRS. Recently published research from the Clark laboratory has demonstrated a proof-of-concept DNA-based sensor for minimally invasive detection of IFN?, one of the cytokines that has been proposed as a biomarker for predicting the potential for onset of severe CRS. This design was inspired by advances in DNA nanotechnology, which enable researchers to create functional nanostructures with site-specific modifications based on the complementary base-pairing rules of DNA. The open or closed state of the sensor could be determined through differential signals as detected with optical imaging. Drawing from recent advances in DNA origami design and stabilization technology, we hypothesize that we can improve on this work and produce a robust platform for optical monitoring of IFN? in real-time by (1) enhancing the rigidity of our DNA platform and (2) deploying protection strategies to ionically stabilize the construct in biological solutions. This project aims to advance current analytical strategies for immunological diagnostics by providing researchers with a powerful tool to probe biomolecule dynamics toward in vivo use with existing optical imaging platforms. The one-year project will result in a robust tool developed for animal research. The goal will be to commercialize and distribute the sensor for COVID-19 studies, as well as other immune system research.